AKAP-Lbc mobilizes a cardiac hypertrophy signaling pathway.
Elevated catecholamines in the heart evoke transcriptional activation of the Myocyte Enhancer Factor (MEF) pathway to induce a cellular response known as pathological myocardial hypertrophy. We have discovered that the A-Kinase Anchoring Protein (AKAP)-Lbc is upregulated in hypertrophic cardiomyocytes. It coordinates activation and movement of signaling proteins that initiate MEF2-mediated transcriptional reprogramming events. Live-cell imaging, fluorescent kinase activity reporters, and RNA interference techniques show that AKAP-Lbc couples activation of protein kinase D (PKD) with the phosphorylation-dependent nuclear export of the class II histone deacetylase HDAC5. These studies uncover a role for AKAP-Lbc in which increased expression of the anchoring protein selectively amplifies a signaling pathway that drives cardiac myocytes toward a pathophysiological outcome.
Carnegie
Graeme K
GK
Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Soughayer
Joseph
J
Smith
F Donelson
FD
Pedroja
Benjamin S
BS
Zhang
Fang
F
Diviani
Dario
D
Bristow
Michael R
MR
Kunkel
Maya T
MT
Newton
Alexandra C
AC
Langeberg
Lorene K
LK
Scott
John D
JD
D048948:14-3-3 Proteins / Q000378:metabolism; D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D006332:Cardiomegaly / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D064326:MEF2 Transcription Factors; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction
D048948:14-3-3 Proteins; D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D020662:Guanine Nucleotide Exchange Factors; D064326:MEF2 Transcription Factors; D015778:Minor Histocompatibility Antigens; D018006:Myogenic Regulatory Factors; D011518:Proto-Oncogene Proteins; D010656:Phenylephrine; C089212:protein kinase D; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases